The concept of MolecularMD grew out of discussions with Oregon Health Science University (OHSU) investigators, where the... Read More >   Chronic Myelogenous Leukemia (CML) Overview Chronic myelogenous leukemia (CML) is a rare blood disorder characterized by an expansion of progenitor and mature myeloid cells. In more than 95% of CML cases, there is a reciprocal translocation between chromosomes 9 and 22 that creates a diagnostic cytogenetic abnormality (Philadelphia chromosome). At the molecular level, this translocation fuses the BCR gene with the ABL tyrosine kinase gene. The resulting fusion gene product, BCR-ABL, has disregulated (overactive) tyrosine kinase activity that drives the growth of CML cells. Imatinib (Gleevec ® ; Novartis) is an inhibitor of BCR-ABL tyrosine kinase approved by the FDA for the treatment of patients with CML. Why measure BCR-ABL RNA levels? Serial analysis of BCR-ABL mRNA levels in the blood by real-time quantitative polymerase chain reaction (RQ-PCR) before and after therapy treatment (imatinib or bone marrow transplantation) accurately reflects the level of disease suppression and is an effective method for monitoring treatment efficacy. The National Comprehensive Cancer Network (NCCN) practice guidelines for CML patient management call for measurement of BCR-ABL mRNA levels at initial diagnosis and during subsequent therapeutic monitoring of CML patients. The importance of high quality, reproducible RQ-PCR for measuring BCR-ABL mRNA was emphasized in a consensus publication from a 2005 meeting of thought leaders in the CML field. Why test for BCR-ABL mutations? Over 20 clinical secondary mutations in kinase domain of BCR-ABL have been identified in CML patients who develop resistance to imatinib treatment. Testing for such mutations may be helpful in determining optimal dosing of imatinib, and in evaluating patients entering clinical trials for novel ABL kinase inhibitors. References • Mauro, MJ, and Druker, BJ. Chronic Myelogenous Leukemia. Current Opinion in Oncology. 2001; 13(1):3-7. • Wong, S, and Witte , ON . The BCR-ABL S tory : Bench to Bedside and Back. Annual Review of Immunology. 2004;22:247-306. • Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037. • Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002; 346:645-652. • Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002; 99:1928-1937. • Druker BJ, Talpaz M, Resta DJ, Peng B , Buchdunger E, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 2001;344:1031–37. • Lahay T, Riehm, B, Berger, U et al. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer. 2005;103(8):1659-69. • Goldman JM, Hughes T, Branford S, Radich JP, Druker BJ, et al. CML diagnostic consensus meeting. Betheda. 2005. • S Branford, T P Hughes and Z Rudzki. Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. British Journal of Haematology. 1999; 107 :587–599. • Radich JP. Molecular measurement of minimal residual disease in Philadelphia-positive acute lymphoblastic leukaemia. Best Practice and research clinical hematology. 2002;15(1):91-103. • NCCN. Clinical Practice Guidelines in Oncology; Chronic Myelogenous Leukemia. Version 1. 2006.